The present invention relates to a method of treating migraine in a mammal, including a human, by administering to the mammal a 5HT1 receptor agonist and caffeine in combination with a cyclooxygenase-2 (COX-2) inhibitor. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a 5HT1 receptor agonist and a COX-2 inhibitor. Examples of agonists of 5HT1 receptors are agonists of one or more of the 5HT1A, 5HT1B, 5HT1C, 5HT1D, 5HT1E, and 5HT1F receptors.
The combined use of 5HT1 agonists (e.g. eletriptan, rizatriptan, naratriptan, sumatriptan, zolmitriptan), caffeine and a COX-2 inhibitor for the acute treatment of migraine offers enhanced efficacy than currently used therapies.
Symptomatic treatment helps relieve the pain associated with migraine.
Abortive treatment targets the pathophysiology of migraine and decreases many of the symptoms of migraine, including pain, nausea, photophobia and phonophobia.
NSAIDS have been shown to help in the symptomatic treatment of migraine headache. Its combination with the abortive treatment of the 5HT1 agonists is expected to provide an additional effect than the use of either treatment alone.
COX-2 inhibitors have evolved from the NSAIDS and are expected to have similar efficacy with additional safety and tolerability. By selectively inhibiting the COX-2 isoenzyme associated with inflammation and pain, COX-2 inhibitors would be expected to decrease migraine pain with less or no effect on the COX-1 isoenzyme. This isoenzyme maintains gastrointestinal and renal environments. The effect of the NSAIDS on the COX-1 isoenzyme is thought to be responsible for the large incidence of gastrointestinal and renal adverse experiences associated with NSAIDS treatment. Therefore, the use of the COX-2 inhibitors is advantageous with its additional safety and tolerability.
Caffeine has been found to be an analgesic adjuvant for numerous conditions including headache and pain (see Laska et al., JAMA, Vol. 252, 1711-1718 (1984), which is incorporated by reference in its entirety).
The present invention relates to pharmaceutical compositions for the treatment of migraine in a mammal, including a human, comprising a 5HT1 receptor agonist or a pharmaceutically acceptable salt thereof, and caffeine with
(a) a compound of the formula: 
xe2x80x83or the pharmaceutically acceptable salts thereof wherein
R1 is hydrogen or C1-4 alkyl; R2 is C(xe2x95x90Lxe2x80x2)R3 or SO2R4; Y is a direct bond or C1-4 alkylene; L and Lxe2x80x2 are independently oxygen or sulfur;
Q is selected from the following:
(Q-a) C1-6 alkyl,
(Q-b) halo-substituted C1-4 alkyl,
(Q-c) C3-7 cycloalkyl optionally substituted with one or two substituents independently selected from C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkoxy, hydroxy and halo,
(Q-d) phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, nitro, halo-substituted C1-4 alkoxy, S(O)mR5, SO2NH2, SO2N(C1-4 alkyl)2, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino, NR1C(O)R5, CN, C1-4 alkyl-OH and C1-4 alkyl-OR5,
(Q-e) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic armomatic group being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino, C1-4 alkyl-OH and C1-4 alkyl-OR5, and
(Q-f) a 6-membered monocyclic aromatic group containing one nitrogen atom and optionally containing one, two or three additional nitrogen atom(s), and said monocyclic armomatic group being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino, C1-4 alkyl-OH and C1-4 alkyl-OR5;
R3 is xe2x80x94OR6, xe2x80x94NR7R8, N(OR1)R7 or a group of formula: 
Z is a direct bond, oxygen, sulfur or NR5;
R4 is C1-6 alkyl, halo-substituted C1-4 alkyl, C1-4 alkyl-OH, xe2x80x94NR7R8, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substitutued C1-4 alkyl, hydroxy, C1-4 alkoxy and halo-substitutued C1-4 alkoxy;
R5 is C1-4 alkyl or halo-substituted C1-4 alkyl;
R6 is C1-4 alkyl, C3-7 cycloalkyl, C1-4 alkyl-C3-7 cycloalkyl, halo-substitutued C1-4 alkyl, C1-4 alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, amino, di-(C1-4 alkyl)amino and nitro;
R7 and R8 are independently selected from the following:
(a) hydrogen,
(b) C1-6 alkyl optionally substituted with a substituent independently selected from halo, hydroxy, C1-4 alkoxy, amino, C1-4 alkylamino and di-(C1-4 alkyl)amino,
(c) C3-7 cycloalkyl optionally substituted with a substituent independently selected from hydroxy, C1-4 alkyl and C1-4 alkoxy,
(d) C1-4 alkyl-C3-7 cycloalkyl optionally substituted with a substituent independently selected from hydroxy, C1-4 alkyl and C1-4 alkoxy, and
(f) C1-4 alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, C1-4 alkyl, halo-substitutued C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, nitro, amino, di-(C1-4 alkyl)amino and CN;
X is independently selected from halo, C1-4 alkyl, halo-substitutued C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substitutued C1-4 alkoxy, C1-4 alkylthio, nitro, amino, di-(C1-4 alkyl)amino and CN;
m is 0, 1 or 2; n is 0, 1, 2 or 3; and r is 1, 2 or 3; or
(b) a compound of the formula: 
xe2x80x83or its pharmaceutically acceptable salt thereof, wherein the variables of formula XX are defined as follows;
A is partially unsaturated or unsaturated five membered heterocyclic, or partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula (I) are attached to ring atoms of Ring A adjacent to each other;
R1 is aryl or heteroaryl, and the aryl or heteroaryl being optionally substituted by one to four substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkoxy, C1-4 alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R1 is heteroaryl;
R2 is C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkylamino, C1-4 dialkylamino or amino;
R3, R4 and R5 are independently hydrogen, halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, hydroxy-C1-4 alkyl, C1-4 alkoxy C1-4 alkyl, C1-4 alkanoyl, cyano, nitro, cyano C1-4 alkyl, carboxy, C1-4 alkoxycarbonyl, aminocarbonyl, Nxe2x80x94C1-4 alkylaminocarbonyl, N,N-di-C1-4 alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, Nxe2x80x94C1-4 alkyl-N-arylamiocarbonyl, aryl, aryloxy, aryloxy-C1-4 alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-C1-4 alkyl, morpholino-carbonyl, C1-4 alkoxyaminocarbonyl or C1-4 alkyl-carbonylamino; or two of R3, R4 and R5 are taken together with atoms to which they are attached and form a 4-7 membered ring;
R6 and R7 are independently hydrogen, halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, N,N-di C1-4 alkylamino, hydroxyl-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkyl-C1-4 alkoxy, C1-4 alkylamino-C1-4 alkyl, hydroxy, amino-C1-4 alkyl and N,N-di C1-4 alkylamino-C1-4 alkyl; and
m and n are independently 1, 2, 3 or 4,
with the proviso that when A contains an oxygen or sulfur heteroatom, one of R3, R4 or R5 is absent; or
(c) a compound of the formula: 
xe2x80x83or a pharmaceutically acceptable salt thereof, wherein variables of formula XXX are defined as follows;
Ar is heteroaryl selected from a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
X1 is independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [Nxe2x80x94(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, Nxe2x80x94(C1-C4 alkanoyl)amino, Nxe2x80x94(C1-C4 alkyl)-Nxe2x80x94(C1-C4 alkanoyl)amino, Nxe2x80x94[(C1-C4 alkyl)sulfonyl]amino, N-[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94(C1-C4 alkyl)amino]sulfonyl and [N,N-di(C1-C4 alkyl)amino]sulfonyl;
X2 is independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [Nxe2x80x94(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, Nxe2x80x94(C1-C4 alkanoyl)amino, Nxe2x80x94(C1-C4 alkyl)-Nxe2x80x94(C1-C4 alkanoyl)amino, N-[(C1-C4 alkyl)sulfonyl]amino, N-[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94(C1-C4 alkyl)amino]sulfonyl and [N,N-di(C1-C4 alkyl)amino]sulfonyl;
R1 is selected from
hydrogen;
straight or branched C1-C4 alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
C3-C8 cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
C4-C8 cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [Nxe2x80x94(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, Nxe2x80x94(C1-C4 alkanoyl)amino, N-[(C1-C4 alkyl)(C1-C4 alkanoyl)]amino, N-[(C1-C4 alkyl)sulfonyl]amino, N-[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94(C1-C4 alkyl)amino]sulfonyl and [N,N-di(C1-C4 alkyl)amino]sulfonyl; and
heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and
said heteroaryl being optionally substituted with one to three substituent(s) selected from X1;
R2 and R3 are independently selected from:
hydrogen;
halo;
C1-C4 alkyl;
phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
or R1 and R2 can form, together with the carbon atom to which they are attached, a C3-C7 cycloalkyl ring;
m is 0, 1, 2, 3, 4 or 5; and
n is 0, 1, 2, 3 or 4; or
(d) a compound of the formula: 
xe2x80x83or the pharmaceutically acceptable salts thereof wherein the variables of formula XL are as defined as follows;
Z is OH, C1-6 alkoxy, xe2x80x94NR2R3 or a group of the formula (II) or (III): 
xe2x80x83wherein r is 1, 2, 3 or 4, Y is a direct bond, O, S or NR4, and W is OH or xe2x80x94NR2R3;
Q is selected from the following:
(a) phenyl optionally substituted with one, two or three subsbituents independently selected from
(a-1) halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino, CN, HOxe2x80x94(C1-4) alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, xe2x80x94NH2S(O)2NR2R3, acetyl, xe2x80x94COOH, xe2x80x94C(O)Oxe2x80x94C1-4 alkyl, C1-4 alkylsulfonylamino and C3-7 cycloalkyl,
(a-2) aryl or xe2x80x94Oxe2x80x94(CH2)n-aryl, and the aryl or aryl moiety being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino and CN,
(a-3) 5-membered monocyclic aromatic group optionally substitued with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino and CN,
(a-4) 6-membered monocyclic aromatic group optionally substitued with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino and CN,
(b) a 6-membered monocyclic aromatic group containing one, two, three or four nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group (a-1), (a-2), (a-3) and (a-4),
(c) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group (a-1), (a-2), (a-3) and (a-4);
(d) C3-7 cycloalkyl optionally substituted with one or two substituents independently selected from OH, C1-4 alkyl, halo and halo-substituted C1-4 alkyl; and
(e) a benzo-fuzed heterocycle optionally substituted with one, two or three substituents independently selected from the group (a-1);
R1 is hydrogen, C1-4 alkyl or halo;
R2 and R3 are independently H, OH, C1-4 alkoxy, C1-4 alkyl or C1-4 alkyl substituted with halo, OH, C1-4 alkoxy, NH2 or CN;
R4 is hydrogen or C1-4 alkyl;
X is independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, H, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino, CN, HOxe2x80x94(C1-4)alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, xe2x80x94NH2S(O)2NR2NR3, acetyl, xe2x80x94COOH, xe2x80x94C(O)Oxe2x80x94C1-4 alkyl, C1-4 alkylsulfonylamino and C3-7 cycloalkyl; and
n is 0, 1, 2, 3 or 4; or
(e) a compound of the formula: 
xe2x80x83and the pharmaceutically acceptable salts thereof wherein the compounds of formula L are defined as follows;
Ar is phenyl, C3-8 cycloalkyl, C4-8 cycloalkenyl or heteroaryl which is connected to Y through a carbon atom, the heteroaryl being selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl;
X1 is H, halo, C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkyl, hydroxy-substituted C1-4 alkyl, (C1-4)alkoxy(C1-4)alkyl, amino, C1-4 alkylamino, di(C1-4)alkylamino, amino C1-4 alkyl, (C1-4)alkylamino(C1-4)alkyl, di(1-4)alkylamino(C1-4)alkyl, C1-4 alkanoylamino, di(C1-4)alkanoylamino, (C1-4)alkyl(C1-4 alkanoyl)amino, C1-4 alkylsulfonylamino, C1-4 alkanoyl, carboxyl, (C1-4)alkoxycarbonyl, aminocarbonyl, (C1-4)alkylaminocarbonyl, di(C1-4)alkylaminocarbonyl, cyano, nitro, mercapto, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylaminosulfonyl or di(C1-4)alkylaminosulfonyl;
X2 and X3 are independently C1-4 alkyl, halo, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, mercapto, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-4 alkanoyl, carboxyl, (C1-4)alkoxycarbonyl, aminocarbonyl, C1-4 alkylaminocarbonyl, di(C1-4)alkylaminocarbonyl, cyano, nitro, amino, C1-4 alkylamino, di(C1-4)alkylamino or C1-4 alkylsulfonylamino;
Y is xe2x80x94CR1=CR2- or xe2x80x94Cxe2x89xa1Cxe2x80x94, wherein R1 and R2 are independently H, methyl, ethyl or halo;
l is 0, 1, 2, 3 or 4; and
m and n are independently 0, 1, 2 or 3,
with the proviso that when Ar is phenyl; and l, m and n are O, Y is not xe2x80x94CHxe2x95x90CHxe2x80x94; and when Ar is phenyl; l and m are 0; n is 1; and Y is xe2x80x94CHxe2x95x90CHxe2x80x94, X3 is not C1-4 alkoxy attached to the 2-position of Ar, nor amino, C1-4 alkylamino or di(C1-4)alkylamino attached at the 4-position of Ar; or
(f) a compound of the formula 
xe2x80x83or pharmaceutically acceptable salts thereof wherein:
Xxe2x80x94Yxe2x80x94Zxe2x80x94 is selected from the group consisting of xe2x80x94C(O)xe2x80x94Oxe2x80x94CR5(R5)xe2x80x94 when side b is a double bond, and sides a and c are single bonds; and
R1 is selected from the group consisting of
(a) S(O)2CH3,
(b) S(O)2NH2,
R2 is selected from the group consisting of
(a) C1-6alkyl,
(b) C3, C4, C5, C6 and C7, cycloalkyl,
(c) Heteroaryl
(d) Benzoheteroaryl
(e) Mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of
(1) hydrogen,
(2) halo,
(3) C1-6alkoxy,
(4) C1-6alkylthio,
(5) CN,
(6) CF3,
(7) C1-6alkyl,
(8) N3,
(9) xe2x80x94CO2H,
(10) xe2x80x94CO2xe2x80x94C1-4alkyl,
(11) xe2x80x94C(R5)(R6)xe2x80x94OH,
(12) xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94C1-4alkyl, and
(13) xe2x80x94C1-6alkyl-CO2R5;
R5, R5 and R6 are each independently selected from the group consisting of
(a) hydrogen,
(b) C1-6)alkyl,
or R5 and R6 together with the carbon to which they are attached from a saturated monocyclic carbon ring is 3, 4, 5, 6 or 7 atoms;
and a pharmaceutically acceptable carrier.
As used herein, xe2x80x9chaloxe2x80x9d is fluoro, chloro, bromo or iodo.
As used herein, the term xe2x80x9cC1-4 alkylxe2x80x9d means straight or branched chain saturated radicals of 1 to 4 carbon atoms, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.
As used herein, an example of xe2x80x9cpropylxe2x80x9d is n-propyl and isopropyl.
As used herein, an example of xe2x80x9cbutylxe2x80x9d is n-butyl, isobutyl, sec-butyl and tert-butyl.
As used herein, an example of xe2x80x9calkoxyxe2x80x9d is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
As used herein, an example of xe2x80x9calkylthioxe2x80x9d is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.
As used herein, an example of xe2x80x9cdi-(C1-4 alkyl)aminoxe2x80x9d is dimethylamino, diethylamino, dipropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-butylamino, N-ethyl-N-propylamino, and the like.
As used herein, an example of xe2x80x9cC1-4 alkylaminoxe2x80x9d is methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, and the like.
As used herein, an example of xe2x80x9cHOxe2x80x94(C1-4)alkylxe2x80x9d is hydroxymethyl, hydroxyethyl (e.g., 1-hydroxyethyl and 2-hydroxyethyl), hydroxypropyl (e.g., 1-hydroxypropyl, 2-hydroxypropyl and 3-hydroxypropyl).
As used herein, an example of xe2x80x9cC1-4 alkoxy-C1-4 alkylxe2x80x9d is methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, and the like.
As used herein, the term xe2x80x9chalo-substituted alkylxe2x80x9d refers to an alkyl radical as described above substituted with one or more halogens included, but not limited to, chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like.
As used herein, an example of xe2x80x9chalo-substituted alkoxyxe2x80x9d is chloromethoxy, dichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trichloroethoxy, and the like.
As used herein, the term xe2x80x9cC3-7 cycloalkylxe2x80x9d means carbocyclic radicals, of 3 to 7 carbon atoms, including, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
As used herein, an example of xe2x80x9carylxe2x80x9d is phenyl and naphthyl.
As used herein, a 5-membered monocyclic aromatic group usually has one heteroatom selected from O, S and N in the ring. In addition to said heteroatom, the monocyclic aromatic group may optionally have up to three N atoms in the ring. For example, the 5-membered monocyclic aromatic group includes thienyl, furyl, thiazolyl (e.g., 1,3-thiazolyl, 1,2-thiazolyl), imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl, isoxazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl) and the like.
As used herein, an example of a 6-membered monocyclic aromatic group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (e.g., 1,3,5-triazinyl), tetrazinyl and the like.
As used herein, an example of a benzo-fuzed heterocycle includes quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, isoindolyl, 1H-indazolyl, quinazolinyl, phthalazinyl and the like.
As used herein, an example of (ethyl)(ethoxy)pyridyl includes 3-ethoxy-4-ethyl-2-pyridyl, 4-ethoxy-3-ethyl-2-pyridyl and the like.
As used herein, an example of (chloro)(ethyl)pyridyl includes 3-cloro-4-ethyl-2-pyridyl, 4-cloro-3-ethyl-2-pyridyl and the like.
As used herein, an example of (fluoro)(ethyl)phenyl includes 3-fluoro-4-ethyl-2-pyridyl, 4-fluoro-3-ethyl-2-pyridyl and the like.
This invention also relates to a method of treating migraine in a mammal, including a human, comprising administering to said mammal an amount of a pharmaceutical composition comprising a 5HT1 receptor agonist or a pharmaceutically acceptable salt thereof and caffeine; with
(a) a compound of the formula: 
xe2x80x83or the pharmaceutically acceptable salts thereof wherein
R1 is hydrogen or C1-4 alkyl; R2 is C(xe2x95x90Lxe2x80x2)R3 or SO2R4; Y is a direct bond or C1-4 alkylene; L and Lxe2x80x2 are independently oxygen or sulfur;
Q is selected from the following:
(Q-a) C1-6 alkyl,
(Q-b) halo-substituted C1-4 alkyl,
(Q-c) C3-7 cycloalkyl optionally substituted with one or two substituents independently selected from C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkoxy, hydroxy and halo,
(Q-d) phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, nitro, halo-substituted C1-4 alkoxy, S(O)mR5, SO2NH2, SO2N(C1-4 alkyl)2, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino, NR1C(O)R5, CN, C1-4 alkyl-OH and C1-4 alkyl-OR5,
(Q-e) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic armomatic group being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino, C1-4 alkyl-OH and C1-4 alkyl-OR5, and p2 (Q-f) a 6-membered monocyclic aromatic group containing one nitrogen atom and optionally containing one, two or three additional nitrogen atom(s), and said monocyclic armomatic group being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino, C1-4 alkyl-OH and C1-4 alkyl-OR5;
R3 is xe2x80x94OR6, xe2x80x94NR7R8, N(OR1)R7 or a group of formula: 
Z is a direct bond, oxygen, sulfur or NR5;
R4 is C1-6 alkyl, halo-substituted C1-4 alkyl, C1-4 alkyl-OH, xe2x80x94NR7R3, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substitutued C1-4 alkyl, hydroxy, C1-4 alkoxy and halo-substitutued C1-4 alkoxy;
R5 is C1-4 alkyl or halo-substituted C1-4 alkyl;
R6 is C1-4 alkyl, C3-7 cycloalkyl, C1-4 alkyl-C3-7 cycloalkyl, halo-substitutued C1-4 alkyl, C1-4 alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, C1-4 alkyl, halo-substitutued C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, amino, di-(C1-4 alkyl)amino and nitro;
R7 and R8 are independently selected from the following:
(a) hydrogen,
(b) C1-6 alkyl optionally substituted with a substituent independently selected from halo, hydroxy, C1-4 alkoxy, amino, C1-4 alkylamino and di-(C1-4 alkyl)amino,
(c) C3-7 cycloalkyl optionally substituted with a substituent independently selected from hydroxy, C1-4 alkyl and C1-4 alkoxy,
(d) C1-4 alkyl-C3-7 cycloalkyl optionally substituted with a substituent independently selected from hydroxy, C1-4 alkyl and C1-4 alkoxy, and
(f) C1-4 alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, C1-4 alkyl, halo-substitutued C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, nitro, amino, di-(C1-4 alkyl)amino and CN;
X is independently selected from halo, C1-4 alkyl, halo-substitutued C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substitutued C1-4 alkoxy, C1-4 alkylthio, nitro, amino, di-(C1-4 alkyl)amino and CN;
m is 0, 1 or 2; n is 0, 1, 2 or 3; and r is 1,2 or 3; or
(b) a compound of the formula: 
xe2x80x83or its pharmaceutically acceptable salt thereof, wherein the variables of formula XX are defined as follows;
A is partially unsaturated or unsaturated five membered heterocyclic, or partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula (I) are attached to ring atoms of Ring A adjacent to each other;
R1 is aryl or heteroaryl, and the aryl or heteroaryl being optionally substituted by one to four substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkoxy, C1-4 alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R1 is heteroaryl;
R2 is C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkylamino, C1-4 dialkylamino or amino;
R3, R4 and R5 are independently hydrogen, halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, hydroxy-C1-4 alkyl, C1-4 alkoxy C1-4 alkyl, C1-4 alkanoyl, cyano, nitro, cyano C1-4 alkyl, carboxy, C1-4 alkoxycarbonyl, aminocarbonyl, Nxe2x80x94C1-4 alkylaminocarbonyl, N,N-di-C1-4 alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, N-C1-4 alkyl-N-arylamiocarbonyl, aryl, aryloxy, aryloxy-C1-4 alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-C1-4 alkyl, morpholino-carbonyl, C1-4 alkoxyaminocarbonyl or C1-4 alkyl-carbonylamino; or two of R3, R4 and R5 are taken together with atoms to which they are attached and form a 4-7 membered ring;
R6 and R7 are independently hydrogen, halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, N,N-di C1-4 alkylamino, hydroxyl-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkyl-C1-4 alkoxy, C1-4 alkylamino-C1-4 alkyl, hydroxy, amino-C1-4 alkyl and N,N-di C1-4 alkylamino-C1-4 alkyl; and
m and n are independently 1, 2, 3 or 4,
with the proviso that when A contains an oxygen or sulfur heteroatom, one of R3, R4 or R5 is absent; or
(c) a compound of the formula: 
xe2x80x83or a pharmaceutically acceptable salt thereof, wherein variables of formula XXX are defined as follows;
Ar is heteroaryl selected from a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
X1 is independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [Nxe2x80x94(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, Nxe2x80x94(C1-C4 alkanoyl)amino, Nxe2x80x94(C1-C4 alkyl)-Nxe2x80x94(C1-C4 alkanoyl)amino, N-[(C1-C4 alkyl)sulfonyl]amino, Nxe2x80x94[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94(C1-C4 alkyl)amino]sulfonyl and [N,N-di(C1-C4 alkyl)amino]sulfonyl;
X2 is independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [Nxe2x80x94(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, Nxe2x80x94(C1-C4 alkanoyl)amino, Nxe2x80x94(C1-C4 alkyl)-Nxe2x80x94(C1-C4 alkanoyl)amino, N-[(C1-C4 alkyl)sulfonyl]amino, N-[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94(C1-C4 alkyl)amino]sulfonyl and [N,N-di(C1-C4 alkyl)amino]sulfonyl;
R1 is selected from
hydrogen;
straight or branched C1-C4 alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
C3-C8 cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
C4-C8 cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N, N-di(C1-C4 alkyl)amino, [Nxe2x80x94(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, Nxe2x80x94(C1-C4 alkanoyl)amino, Nxe2x80x94[(C1-C4 alkyl)(C1-C4 alkanoyl)]amino, Nxe2x80x94[(C1-C4 alkyl)sulfonyl]amino, N-[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94(C1-C4 alkyl)amino]sulfonyl and [N,N-di(C1-C4 alkyl)amino]sulfonyl; and
heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and
said heteroaryl being optionally substituted with one to three substituent(s) selected from X1;
R2 and R3 are independently selected from:
hydrogen;
halo;
C1-C4 alkyl;
phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
or R1 and R2 can form, together with the carbon atom to which they are attached, a C3-C7 cycloalkyl ring;
m is 0, 1, 2, 3, 4 or 5; and
n is 0, 1, 2, 3 or 4; or
(d) a compound of the formula: 
xe2x80x83or the pharmaceutically acceptable salts thereof wherein the variables of formula XL are as defined as follows;
Z is OH, C1-6 alkoxy, xe2x80x94NR2R3 or a group of the formula (II) or (III): 
xe2x80x83wherein r is 1, 2, 3 or 4, Y is a direct bond, O, S or NR4, and W is OH or xe2x80x94NR2R3;
Q is selected from the following:
(a) phenyl optionally substituted with one, two or three substituents independently selected from
(a-1) halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino, CN, HOxe2x80x94(C1-4) alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, xe2x80x94NH2S(O)2NR2R3, acetyl, xe2x80x94COOH, xe2x80x94C(O)Oxe2x80x94C1-4 alkyl, C1-4 alkylsulfonylamino and C3-7 cycloalkyl,
(a-2) aryl or xe2x80x94Oxe2x80x94(CH2)n-aryl, and the aryl or aryl moiety being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di(C1-4 alkyl)amino, C1-4 alkylamino and CN,
(a-3) 5-membered monocyclic aromatic group optionally substitued with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino and CN,
(a-4) 6-membered monocyclic aromatic group optionally substitued with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino and CN,
(b) a 6-membered monocyclic aromatic group containing one, two, three or four nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group (a-1), (a-2), (a-3) and (a-4),
(c) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group (a-1), (a-2), (a-3) and (a-4);
(d) C3-7 cycloalkyl optionally substituted with one or two substituents independently selected from OH, C1-4 alkyl, halo and halo-substituted C1-4 alkyl; and
(e) a benzo-fuzed heterocycle optionally substituted with one, two or three substituents independently selected from the group (a-1);
R1 is hydrogen, C1-4 alkyl or halo;
R2 and R3 are independently H, OH, C1-4 alkoxy, C1-4 alkyl or C1-4 alkyl substituted with halo, OH, C1-4 alkoxy, NH2 or CN;
R4 is hydrogen or C1-4 alkyl;
X is independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino, CN, HOxe2x80x94(C1-4)alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, xe2x80x94NH2S(O)2NR2NR3, acetyl, xe2x80x94COOH, xe2x80x94C(O)Oxe2x80x94C1-4 alkyl, C1-4 alkylsulfonylamino and C3-7 cycloalkyl; and
n is 0, 1, 2, 3 or 4; or
(e) a compound of the formula: 
xe2x80x83and the pharmaceutically acceptable salts thereof wherein the compounds of formula L are defined as follows;
Ar is phenyl, C3-8 cycloalkyl, C4-8 cycloalkenyl or heteroaryl which is connected to Y through a carbon atom, the heteroaryl being selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl;
X1 is H, halo, C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkyl, hydroxy-substituted C1-4 alkyl, (C1-4)alkoxy(C1-4)alkyl, amino, C1-4 alkylamino, di(C1-4)alkylamino, amino C1-4 alkyl, (C1-4)alkylamino(C1-4)alkyl, di(C1-4)alkylamino(C1-4)alkyl, C1-4 alkanoylamino, di(C1-4)alkanoylamino, (C1-4)alkyl(C1-4 alkanoyl)amino, C1-4 alkylsulfonylamino, C1-4 alkanoyl, carboxyl, (C1-4)alkoxycarbonyl, aminocarbonyl, (C1-4)alkylaminocarbonyl, di(C1-4)alkylaminocarbonyl, cyano, nitro, mercapto, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylaminosulfonyl or di(C1-4)alkylaminosulfonyl;
X2 and X3 are independently C1-4 alkyl, halo, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, mercapto, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-4 alkanoyl, carboxyl, (C1-4)alkoxycarbonyl, aminocarbonyl, C1-4 alkylaminocarbonyl, di(C1-4)alkylaminocarbonyl, cyano, nitro, amino, C1-4 alkylamino, di(C1-4)alkylamino or C1-4 alkylsulfonylamino;
Y is xe2x80x94CR1=CR2- or xe2x80x94Cxe2x89xa1Cxe2x80x94, wherein R1 and R2 are independently H, methyl, ethyl or halo;
l is 0, 1, 2, 3 or 4; and
m and n are independently 0, 1, 2 or 3,
with the proviso that when Ar is phenyl; and l, m and n are 0, Y is not xe2x80x94CHxe2x95x90CHxe2x80x94; and when Ar is phenyl; l and m are 0; n is 1; and Y is xe2x80x94CHxe2x95x90CHxe2x80x94, X3 is not C1-4 alkoxy attached to the 2- position of Ar, nor amino, C1-4 alkylamino or di(C1-4)alkylamino attached at the 4-position of Ar; or
(f) a compound of the formula 
xe2x80x83or pharmaceutically acceptable salts thereof wherein:
Xxe2x80x94Yxe2x80x94Zxe2x80x94 is selected from the group consisting of xe2x80x94C(O)xe2x80x94Oxe2x80x94CR5(R5)xe2x80x94 when side b is a double bond, and sides a and c are single bonds; and
R1 is selected from the group consisting of
(c) S(O)2CH3,
(d) S(O)2NH2,
R2 is selected from the group consisting of
(e) C1-6alkyl,
(f) C3, C4, C5, C6 and C7, cycloalkyl,
(g) Heteroaryl
(h) Benzoheteroaryl
(e) Mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of
(14) hydrogen,
(15) halo,
(16) C1-6alkoxy,
(17) C1-6alkylthio,
(18) CN,
(19) CF3,
(20) C1-6alkyl,
(21) N3,
(22) xe2x80x94CO2H,
(23) xe2x80x94CO2xe2x80x94C1-4alkyl,
(24) xe2x80x94C(R5)(R6)xe2x80x94OH,
(25) xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94C1-4alkyl, and
(26) xe2x80x94C1-6alkyl-CO2R5;
R5, R5 and R6 are each independently selected from the group consisting of
(c) hydrogen,
(d) C1-6)alkyl,
or R5 and R6 together with the carbon to which they are attached from a saturated monocyclic carbon ring is 3, 4, 5, 6 or 7 atoms;
and a pharmaceutically acceptable carrier, that is effective in treating migraine.
This invention also relates to a method of treating migraine in a mammal, including a human, comprising administering to said mammal a 5HT1 receptor agonist, or a pharmaceutically acceptable salt thereof, caffeine and a cyclooxygenase-2 (COX-2) inhibitor in amounts that render the combination of such three active agents effective in the treatment or prevention of migraine.
Preferred embodiments of this invention relate to pharmaceutical compositions for the treatment of migraine and methods of treating migraine, as described above, wherein the 5HT1 receptor agonist is selected from eletriptan, naratriptan, rizatriptan, sumatriptan almotriptan, avitriptan, frovatriptan, alniditan, zolmitriptan, LY 334370, LY 306258, BMS-180048 and BMS-181885.
Other embodiments of this invention relate to pharmaceutical compositions for the treatment of migraine and methods of treating migraine, as described above, wherein the 5HT1 receptor agonist is a compound of the formula 
xe2x80x83wherein R3, R4, and Z are selected, independently, from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), (C1-C4)alkyl optionally substituted with from one to three fluorine atoms, (C1-C4)alkoxy optionally substituted with from one to three fluorine atoms, and (C1-C4)alkoxy-(C1-C4)alkyl wherein each of the alkyl moieties may optionally be substituted with from one to three fluorine atoms;
W is xe2x80x94CH2xe2x80x94Oxe2x80x94(C1-C6)alkyl wherein the alkyl moiety can be straight or branched;
or W is xe2x80x94CH2NR1R2 wherein R1 and R2 are independently selected from hydrogen and straight or branched (C1-C6)alkyl;
or R1 and R2, together with the nitrogen to which they are attached, form a saturated four membered monocyclic ring or a saturated or unsaturated nonaromatic five to seven membered monocyclic ring or a saturated or unsaturated nonaromatic seven to ten membered bicyclic ring which may optionally contain one or two heteroatoms in addition to the nitrogen of NR1R2, wherein said heteroatoms are independently selected from oxygen, nitrogen and sulfur, and wherein from one to three of the ring carbon atoms, or one of the ring nitrogen atoms, may optionally and independently be substituted with straight or branched (C1-C4)alkyl, straight or branched (C1-C6)alkoxy, straight or branched (C1-C3)alkyl-(C3-C7)cycloalkyl, hydroxy, amino, cyano, halo, aryl-(straight or branched (C1-C3)alkyl) or heteroaryl-(straight or branched (C1-C3)alkyl), wherein said aryl is selected from phenyl and naphthyl and said heteroaryl is selected from oxazolyl, isoxazoyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyrazinyl, pyrazolyl, indolyl, isoindolyl, pyrazinyl, cinnolinyl, pyridinyl and pyrimidinyl;
with the proviso that in any ring formed by NR1R2: (a) there can be no more than one ring oxygen atom; (b) there can be no hydroxy, alkoxy, alkoxyalkyl, cyano, amino or alkylamino moiety bonded directly to any ring nitrogen atom; and (c) no ring carbon that is double bonded to another ring carbon and not part of an aromatic ring system can be bonded to a ring oxygen atom or ring nitrogen atom;
or a pharmaceutically acceptable salt thereof.